ABSTRACT. Deregulation of cardiac miRNA gene-regulatory networks is a feature of different heart diseases, including ischemic (ICM) and nonischemic (NICM) cardiomyopathy. Here, based on the paired miRNA and mRNA expression profiles in ICM and NICM, we identified the differentially expressed miRNAs and mRNAs and the expression signatures distinguishing ICM/NICM from control samples. Furthermore, we constructed a functional miRNA network for each disease. Analysis of the topological features of these networks revealed that the Wnt signaling pathway and cell cycle (de)regulation play critical roles in the development of ICM and NICM. In addition, comparison of the miRNA and mRNA functional profiles revealed that their expression patterns in ICM and NICM differ. These findings revealed hundreds of novel heart-failurerelated miRNAs with important regulatory functions. In summary, RNA- seq-based transcriptome profiling in the failing human heart revealed a complex transcriptional regulation associated with the disease. The newly uncovered importance of miRNAs in disease pathogenesis highlights their value as potential diagnostic and therapeutic targets.